Over the past decade there has been great interest in limiting infarct size in severly ischemic myocardium. Recently, acute reperfusion of ischemic myocardium has been achieved in both the operating room and the catheterization laboratory. While the overall results are encouraging, it is clear from clinical and basic studies that reperfusion has potentially detrimental effects. We have demonstrated that acute reperfusion is associated with a substantial increase in intracellular edema which is accompanied by a perfusion deficit. The extent of edema correlates closely with the extent of eventual necrosis. It is possible by raising the osmolality of the perfusate to reduce both the associated intracellular edema and the perfusion deficit and to diminish substantially the extent of eventual necrosis. It is planned in the proposed study to determine the optimal approach or approaches to minimize these deleterious effects of reperfusion. Anesthetized, thoracotomized dogs with appropriate control of the associated hemodynamic conditions will be studied. The studies will be carried out under conditions in which reperfusion is instituted following total interruption of blood flow (absence of collateral blood flow) and following the severly ischemic low flow state. With regard to the latter, we have already demonstrated that prolonged low flow myocardial ischemia without reflow of blood results in cell swelling and a progressive perfusion deficit. Hyperosmotic agents of differing molecular weights will be assessed. In addition, interventions which appear the most promising in salvaging ischemic myocardium will also be evaluated in these models with the hope that a combination of agents might be more effective than a single agent alone in limiting eventual myocardial necrosis. For example, a hyperosmotic agent in combination with a specific non-hyperosmotic agent might produce a greater increase in myocardial salvage than either agent alone. Following initial screening experiments more detailed analysis of early and late morphologic changes will be accomplished. The ultimate goal of these studies is to provide further insight into the pathophysiology of ischemia and to limit the detrimental effects of acute reperfusion on the severly ischemic myocardium and thereby to minimize the extent of eventual myocardial necrosis.